HPV Virus Medical

Accardi L, Dona MG, Di Bonito P, Giorgi C. Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanita, Rome, Italy.

The E7 tumor antigen of human papillomavirus type 16 (HPV16) is a validated target for immunodiagnosis and immunotherapy of HPV-associated cervical cancer. Anti-HPV16 E7 antibodies in scFv format were isolated from a human antibody phage display library and characterized. With the aim of interfering with the oncogenic activity of E7 protein, the most reactive of the selected antibody fragments was expressed by eukaryotic vectors in different compartments of the HPV16-positive cervical carcinoma SiHa cell line. The intracellular antibodies (intrabodies) were tested for their ability of inhibiting cell proliferation. A significant inhibition was obtained targeting the intrabodies to the nuclear and secretory compartments whereas no significant effect was observed in case of cytoplasmic localization. Inhibition was highly specific as no antiproliferative effect was obtained either with the E7-specific intrabodies in HPV-negative cells nor with irrelevant intrabodies in SiHa cells. (c) 2005 Wiley-Liss, Inc.

J Histochem Cytochem. 2005 Apr;53(4):509-16.

Immunohistochemical expression of p16INK4a and bcl-2 according to HPV type and to the progression of cervical squamous intraepithelial lesions.

Guimaraes MC, Goncalves MA, Soares CP, Bettini JS, Duarte RA, Soares EG. Department of Pathology, School of Medicine of Ribeirao Preto, University of Sao Paulo Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil. epigin@uol.com.br

Inactivation of the cell cycle inhibitor gene p16MTS1 seems to be involved in human papillomavirus (HPV)-related carcinogenesis because E6 and E7 oncoproteins may impair p16INK4a and, indirectly, bcl-2 functions. In this study, we analyzed the role of immunohistochemical expression of p16INK4a and bcl-2 in HPV-infected cervical biopsies as prognostic markers of the progression of squamous intraepithelial lesion (SIL). Sixty-five cervical biopsies were stratified into two subgroups according to the second biopsy: 27 of them maintained a low-grade (LG)-SIL diagnosis, and 38 progressed from LG-SIL to high-grade (HG)-SIL. p16INK4a and bcl-2 quantitative expression levels were measured by the immunoperoxidase method. PCR-DNA techniques were used to detect and type HPV. The Wilcoxon and Fisher exact tests were employed for the statistical analysis. In the group with an LG-SIL diagnosis at the second biopsy, no significant associations were found between p16INK4a and bcl-2 expression and presence of HPV16/18. In the group that progressed to HG-SIL, a significant association was observed between p16INK4a overexpression and HPV16/18 presence (p=0.021), but none with bcl-2 levels. It is concluded that immunohistochemical bcl-2 expression may not be useful for predicting the progression of HPV-related SIL. In contrast, p16INK4a overexpression seemed to be associated with HPV 16 and 18, suggesting that it may be a good marker for predicting SIL progression.

Int J Cancer. 2005 Apr 7; [Epub ahead of print]

A cluster randomized controlled trial of visual, cytology and human papillomavirus screening for cancer of the cervix in rural India.

Sankaranarayanan R, Nene BM, Dinshaw KA, Mahe C, Jayant K, Shastri SS, Malvi SG, Chinoy R, Kelkar R, Budukh AM, Keskar V, Rajeshwarker R, Muwonge R, Kane S, Parkin DM. Screening Group, International Agency for Research on Cancer, Lyon, France.

The impact of screening by visual inspection with acetic acid (VIA), cytology or HPV testing on cervical cancer incidence and mortality is investigated in a cluster randomized controlled trial in India. We report findings after the screening phase, when 52 clusters, with a total of 142,701 women aged 30-59 years in Osmanabad District, India, were randomized into 4 arms for a single round of screening by trained midwives with either VIA, cytology or HPV testing as well as a control group. All laboratory tests were done locally. Test-positive women underwent investigations (colposcopy/biopsy) and treatment in the base hospital. Data on participation, test positivity, positive predictive value and detection rates of cervical neoplasia were analyzed using cluster design methodology. Of the eligible women, 72-74% were screened. Test positivity rates were 14.0% for VIA, 7.0% for cytology and 10.3% for HPV. The detection rate of high-grade lesions was similar in all intervention arms (0.7% for VIA, 1.0% for cytology and 0.9% for HPV testing) (p = 0.06, Mann-Whitney test). While the detection rate for VIA dropped to 0.5% with declining test positivity during the course of the study, it remained constant for cytology and HPV testing. Over 85% of women with high-grade lesions received treatment. Our results show that a high level of participation and good-quality cytology can be achieved in low-resource settings. VIA is a useful alternative but requires careful monitoring. Detection rates obtained by HPV testing were similar to cytology, despite higher investments. (c) 2005 Wiley-Liss, Inc.

Anticancer Res. 2005 Mar-Apr;25(2B):1219-23.

Cancer in first degree relatives of Latin American women with cervical cancer. A pilot study.

Weber W, De Sabata MS, Paredes RM, Rodriguez G, Santos C, Sabillon JU, Zwahlen M. Medical Oncology, University of Basel, Basel, Switzerland. cancer@bluewin.ch

BACKGROUND: Cervical cancer is the most frequent cancer of women in Latin America, being strongly associated with infection by certain human papillomavirus (HPV) types. Familial cancer clustering can be due to interactions between infectious agents and host genes. MATERIALS AND METHODS: A cancer-related family history of first degree relatives was elicited in 335 women with invasive cervical cancer (probands) and in 335 women without cancer (controls) in Honduras, Peru and Uruguay, and the frequency of reported familial cancers among the relatives was compared between proband and control relatives. RESULTS: The mean age at the time of interview was 49.8 years for the probands and 50.1 years for the controls (NS). 3852 proband relatives had 114 primary cancers of the following major localisations: 22 uterus, 16 lung, 12 stomach and 64 others. 3333 control relatives had 101 primary cancers of the following major localizations: 18 uterus, 13 stomach, 12 breast, 11 intestinal, 10 lung and 37 others. The frequency of all cancer diagnosis among proband relatives was similar to the frequency among control relatives (odds ratio= 1.01; 95% confidence interval: 0.69-1.47). Nine haemolymphatic malignancies were reported among proband relatives versus 2 in control relatives (odds ratio=3.46; 95% confidence interval: 0.74-16.29). CONCLUSION: All cancer combined did not appear to be more frequent in first degree relatives of women with cervical cancer diagnosis, but haemolymphatic malignancies, a minor part of the cancer burden, may be overrepresented in relatives of women with cervical cancer, pointing to a pathogenic role of familial e.g. hereditary, immunosuppression.

Zhonghua Yi Xue Za Zhi. 2005 Feb 16;85(6):400-4.

Detection of integration status of human papillomavirus 16 in cervical precancerous lesions

HPV Virus Medical - Article in Chinese

OBJECTIVE: To investigate the prevalence of integration of human papillomavirus 16 (HPV16) DNA into the host genome in cervical squamous intraepithelial lesions (SIL). METHODS: Multiplex PCR was used to detect the HPV/HPV16 infection and integration status of HPV16 in the surplus cells from liquid-based cytological samples from 108 patients with cervical cancer precursor lesions. Consensus primers GP5+/GP6+ were used to amplify a 150 bp long fragment in the conserved region of the HPV L1 gene so as to detect the presence pf HPV. Scion Image 4.0 electrophoresis image analysis soft was used to calculate the E2/E6 ratio so as to evaluate the episomal and integrated status of HPV16 infection: in episomal form, both targets should be equivalent, and in integrated form, E2 gene would be absent, while in mixed form of episomal/integrated mixed form, the copy number of E2 would be less than that of E6. RESULTS: Sixty-two out of the 108 patients (57.41%) had HPV infection. HPV16 were found in 32 of the 108 samples (29.63%). Among the 32 cases HPV16 DNA was exclusively episomal in 15 cases (46.88%), concomitant in 13 cases (40.62%), and integrated in 4 cases (12.50%). The prevalence of integrated and/or concomitant forms of HPV-16 DNA increased with progression of cervical disease. The prevalence of integrated form was 54.55% in the patients of CIN3 type, 50.00% in CIN2 type, 28.07% in CIN1 type, and 11.54% in the inflammatory type with significant differences between any 2 groups (all P < 0.01). CONCLUSIONS: HPV16 integration into the host genome is already present in some of CIN lesions. The multiplex PCR estimation of the HPV L1, HPV16 E2, E6 genes and E2/E6 ratio could be a simple method for detecting HPV/HPV16 infection and its integration status in liquid-based residual samples. It would be a helpful complementary tool for cytological screening to identify those patients at high risk of developing high-grade squamous intraepithelial lesions and cervical cancer.

Cancer Epidemiol Biomarkers Prev. 2005 May;14(5):1157-64.

Human papillomavirus genotype distribution in low-grade cervical lesions: comparison by geographic region and with cervical cancer.

Clifford GM, Rana RK, Franceschi S, Smith JS, Gough G, Pimenta JM. IARC, 150 Cours Albert Thomas, F-69372 Lyon cedex 08, France. clifford@iarc.fr.

Low-grade squamous intraepithelial lesions (LSIL) associated with certain human papillomavirus (HPV) genotypes may preferentially progress to cervical cancer. HPV genotyping may thus have the potential to improve the effectiveness of screening programs and to reduce overtreatment. LSIL cases (n = 8,308) from 55 published studies were included in a meta-analysis. HPV genotype distribution was assessed by geographic region and in comparison with published data on cervical squamous cell carcinoma (SCC). HPV detection in LSIL was 80% in North America but less than 70% in other regions, most likely reflecting regional differences in LSIL diagnosis. Among 5,910 HPV-positive LSILs, HPV16 was the most common genotype (26.3%) followed by HPV31 (11.5%), HPV51 (10.6%), and HPV53 (10.2%). HPV-positive LSILs from Africa were 2-fold less likely to be infected with HPV16 than those in Europe, and HPV-positive LSILs from North America were more likely to be infected with HPV18 than those from Europe or South/Central America. Interpretation for rarer genotypes was hampered by variation in HPV testing methodology. SCC/LSIL prevalence ratios indicated that HPV16 was 2-fold and HPV18 was 1.5-fold more common in SCC than in HPV-positive LSIL, thus appearing more likely to progress than other high-risk genotypes (SCC/LSIL prevalence ratios between 0.05 and 0.85). HPV53 and HPV66 showed SCC/LSIL ratios of 0.02 and 0.01, respectively. HPV genotype distribution in LSIL differs from that in cervical cancer, highlighting the importance of HPV genotype in the risk of progression from LSIL to malignancy. Some regional differences in the relative importance of HPV genotypes in LSIL were noted.

Gynecol Oncol. 2005 May 12; [Epub ahead of print]

Psychosocial factors and the course of cervical intra-epithelial neoplasia: A prospective study.

Tiersma ES, van der Lee ML, Garssen B, Peters AA, Visser AP, Fleuren GJ, van Leeuwen KM, le Cessie S, Goodkin K. Helen Dowling Institute, Center for Psycho-oncology, Utrecht, The Netherlands; Department of Obstetrics and Gynecology, Leiden University Medical Center, Leiden, The Netherlands.

OBJECTIVE.: To investigate the influence of psychosocial factors on the course of cervical intra-epithelial neoplasia (CIN). METHODS.: A group of 93 patients with CIN 1 or 2 was followed for 2.25 years by half-yearly colposcopy and cytology. Negatively-rated life events, social support, and coping style were studied in relation to distress during follow-up and in relation to time till progression and regression of CIN. Human papillomavirus (HPV) infection was controlled for as well as sick role bias caused by suspicion of having cervical cancer and distress due to the abnormal cervical smear. RESULTS.: During follow-up, progression was found in 20 patients (22%), stable disease in 22 patients (24%), and regression in 51 patients (55%). Negatively-rated life events and lack of social support predicted distress longitudinally. No association was found between progression or regression of CIN and negatively-rated life events, lack of social support, coping style, and distress. CONCLUSION.: We found no evidence that psychosocial factors influence the course of CIN.

J Virol. 2005 Jun;79(11):6838-47.

Human papillomavirus type 31b infection of human keratinocytes does not require heparan sulfate.

Patterson NA, Smith JL, Ozbun MA. Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131. mozbun@salud.unm.edu.

Oncogenic human papillomaviruses (HPVs) are difficult to study experimentally as they replicate at low levels in vivo. This has precluded the purification of high-risk HPV virions from in vivo lesions. Virus-like particles (VLPs) and pseudovirions from low- and high-risk HPV types can emulate various aspects of HPV virion attachment and infections. These studies suggest that HPV infection is mediated by alpha6-integrin and/or heparan-sulfonated receptors. However, whether VLPs and pseudovirions accurately reflect the infection process of HPV virions has not been verified. We generated infectious HPV31b virions from organotypic (raft) tissues and performed experimental infections in a variety of cells. Successful infection following viral attachment, internalization, and nuclear transport was assayed by detecting newly synthesized, spliced HPV transcripts using reverse transcription (RT)-PCR or RT-quantitative PCR. Most human epithelial cells were infected with HPV31b at a multiplicity of infection as low as 1 to 10 viral genome equivalents per cell. HPV31b infection was detected in other cell lines, including COS-7 monkey kidney cells, but higher viral multiplicities of infection were required. Heparin preparations of various molecular weights or heparinase I treatment of cells prevented HPV31b infection of COS-7 cells and C-33A human cervical cancer cells in reproducible and dose-dependent manners. However, these reagents were unable to block infection of human keratinocytes, including HaCaT and N/TERT-1 cells and low-passage human foreskin keratinocytes. These data suggest that HPV31b infection of human keratinocytes, the natural host cell for HPV infections in vivo, does not require a heparan-sulfonated receptor, whereas heparan sulfate is important for infection of some other cells.

Wiad Lek. 2004;57 Suppl 1:201-6.

Significance of the DNA-HPV research in cervical cancer prevention

HPV Virus Medical - Article in Polish

The purpose of our research was to assess DNA-HPV frequention observation and evaluation of the diagnostic value mRNA E6 and E7 HPV16 and HPV18 profile concentration in prognostic risk of intraepithelial lesions and cervical cancer progression in women with cytological screening. Human papilloma virus (HPV) infection were detected in 13.8% normal samples, presence HPV16 and 18 in 7.5% samples were detected. HPV 16, 18 or HPV16 and 18 infection were detected in 85% HSIL (high-grade squamous intraepithelial lesion) samples. HPV16 or HPV18 infection in 100% cancer samples were detected. In samples from control group expression of E6 and E7 genes were not detected. In LSIL (low-grade squamous intraepithelial lesion) group HPV16 E7 gene in 2.6% samples, in HSIL group E7 gene in 9.5% samples were detected. In all cancer samples E7 or E6 HPV16 and/or HPV18 were detected.

Vaccine. 2005 May 25;23(28):3634-41.

Immune responses induced by lower airway mucosal immunisation with a human papillomavirus type 16 virus-like particle vaccine.

Nardelli-Haefliger D, Lurati F, Wirthner D, Spertini F, Schiller JT, Lowy DR, Ponci F, Grandi PD. Department of Gynecology, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland.

Cervical cancer results from cervical infection by human papillomaviruses (HPV), especially HPV16. Previous studies have shown that intramuscular vaccination of women with an HPV16 virus-like particle (VLP) vaccine induced a strong IgG response and protected against genital HPV16 infection. However, an alternative route of administration that avoids parenteral injection while inducing mucosal immunity might facilitate vaccine implementation in some settings, and partially overcome the substantial variation in HPV16 antibodies at the cervix seen in ovulating women. In this study, women were vaccinated with escalating doses of HPV16L1 VLPs via nasal nebulisation, bronchial aerosolisation, or a combination of intramuscular and aerosol vaccination. The alternative routes of vaccination were well tolerated and many of the volunteers who received aerosol vaccinations exhibited serum antibody titers that were comparable to those induced by intramuscular vaccination. A mucosal immune response was induced by aerosol vaccination as demonstrated by the induction of anti-HPV16 VLP IgA secreting cells in PBMC and SIgA in secretions. Our data suggest that aerosol administration of HPV VLPs may represent a potential alternative to parenteral injection.

J Low Genit Tract Dis. 2004 Jul;8(3):217-223.

Human Papillomavirus and Abnormal Pap Test Results in Vietnamese-American Women: A Pilot Case-Control Study.

Vo PD, Nguyen TT, Nguyen P, Hilton JF, Palefsky JM, Ma Y, McPhee SJ. 1School of Medicine, 2Division of General Internal Medicine and Vietnamese Community Health Promotion Project, 3Department of Epidemiology and Biostatistics, 4Department of Medicine, and 5Department of Adolescent Medicine, University of California, San Francisco, San Francisco, CA; and the 6Santa Clara Valley Health and Hospital System, Santa Clara, CA.

OBJECTIVE.: To evaluate the relationship between abnormal Pap test results and human papillomavirus (HPV) in Vietnamese-American women, who have the highest cervical cancer incidence in the United States. MATERIALS AND METHODS.: In 2001, we obtained specimens from 117 Vietnamese women, 24 with abnormal Pap test results including atypical squamous cells of undetermined significance (cases) and 93 with normal Pap test results (controls), as classified by the 1991 Bethesda System. We used L1 consensus primers MY09/MY11 to perform HPV polymerase chain reaction analysis and type-specific probes to perform genotyping. RESULTS.: Thirteen cases (54%) and 6 controls (6%) were HPV positive (p < .001). Ten of 24 cases (42%) and 0 controls (0%) had high-risk HPV types (16, 18, 45, 53, 56, or 66; p < .001). High-risk HPV types were significantly associated with increasing severity of Pap test results. CONCLUSIONS.: Compared with those with normal Pap test results, Vietnamese-American women with abnormal Pap test results were more likely to have high-risk HPV types. Higher cervical cancer incidence among these women is likely the result of less frequent Pap screening rates and not different biology.

Gynecol Oncol. 2005 May;97(2):342-7.

The expression of MAGE and GAGE genes in uterine cervical carcinoma of Korea by RT-PCR with common primers.

Chang HK, Park J, Kim W, Kim K, Lee M, Park U, Choi B. Department of Pathology, Kosin University Medical College, 34 AmNam-Dong, Suh-Ku, Pusan, 602-702, South Korea.

BACKGROUND: Melanoma antigen genes (MAGE) and GAGE genes are encoded by genes that are silent in virtually all normal adult tissues but are expressed in tumors from various tissues. These gene products are targets for specific immunotherapy as they are presented by HLA I molecules and recognized by autologous cytotoxic T-lymphocytes. However, the characteristics of these genes, especially in uterine cervical cancer are relatively unknown. PURPOSE: This study evaluated the prevalence of MAGE and GAGE by reverse transcription-polymerase chain reaction (RT-PCR) with common primers and discusses clinical implications in cervical carcinoma. MATERIALS AND METHODS: Fresh tissue from 37 cases of primary squamous cell carcinoma and normal cervical mucosa were evaluated for clinicopathologic parameters including Human Papilloma Virus (HPV)-16,18 infection by PCR, tumor stage by FIGO classification and lymph node involvement. RT-nested PCR for the MAGE and GAGE genes was performed with common primers and DNA sequencing after subcloning was used for identification of PCR products of MAGE. Formalin-fixed paraffin embedded material from the same specimen was analyzed by in situ RT-PCR for MAGE. RESULTS: Expression of MAGE and GAGE was not observed in normal tissues. Eleven out of 37 cases expressed MAGE mRNA (29.7%): analysis of subtypes identified one case of MAGE-1, two cases of MAGE-4b, six cases of MAGE-3, and two unknown subtypes. Thirteen out of 37 cases (35.1%) expressed GAGE mRNA. No significant relationships between expression of these genes and FIGO staging, lymph node metastasis or HPV infection were found. CONCLUSION: Expression of MAGE and GAGE may be involved in the development of uterine cervical carcinoma from intraepithelial neoplasia, although without distinct prognostic significance. MAGE and GAGE genes have the potential to be used as targets for the treatment of uterine cervical carcinoma.

Oncogene. 2005 Apr 25; [Epub ahead of print]

Crosstalk between the human papillomavirus E2 transcriptional activator and the E6 oncoprotein.

Grm HS, Massimi P, Gammoh N, Banks L. 1International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34012 Trieste, Italy.

Human papillomaviruses are the causative agents of cervical cancer. Previous studies have shown that loss of the viral E2 protein during malignant progression is an important feature of HPV-induced malignancy due to the resulting uncontrolled expression of the viral oncoproteins E6 and E7. We now show however that the viral E2 and E6 proteins are both capable of regulating each other's activity. When coexpressed, E2 and E6 induce marked changes in the pattern of each other's expression, with preferential accumulation in nuclear speckles. The two proteins interact directly, resulting in changes in the substrate specificities of E6 and the biochemical activities of E2. Thus, while E6 efficiently degrades its PDZ domain-containing substrates in the absence of E2, this activity is greatly diminished when E2 is present. Likewise, E2 alone drives both viral DNA replication and viral gene expression. However, in the presence of E6, viral DNA replication is inhibited while the transcriptional activity of E2 is elevated. These studies define a far more complex pattern of interaction between E2 and E6 than was previously thought and redefines the possible consequences of loss of E2 with respect to uncontrolled E6 activity and consequent malignant progression.Oncogene advance online publication, 25 April 2005; doi:10.1038/sj.onc.1208701.

Am J Clin Pathol. 2005 Feb;123(2):250-5.

A novel filtration-based processing method of liquid cytology specimens for human papillomavirus DNA testing by hybrid capture II.

Castle PE, Garcia-Meijide M, Holladay EB, Chuke R, Payne J, Long A, Siefers H, Demuth F, Lorincz AT. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, Department of Health and Human Services, Bethesda, MD 20892-7234, USA.

We evaluated a more efficient method of processing liquid-based cervical cytology specimens for human papillomavirus (HPV) DNA testing by Hybrid Capture II (HCII). Aliquots were made from 701 specimens in the following sequence: 4.0, 2.0, 1.0, 0.5, and 1.5 mL. The 4.0-mL aliquot was processed by the standard method (STP), and half of the processed material was tested by HCII. Other aliquots were processed with a new, filtration-based processing method (NPM). The 2.0-mL NPM aliquot had HCII test performance most similar to the STP, ie, similar HCII positivity (P = .4) and good test agreement (kappa = 0.85, 95% confidence interval [CI], 0.80-0.89). The 194 cytologic negatives had greater positivity by STP (P = .04) compared with the 2.0-mL aliquot processed by NPM; between-method agreement was modest (kappa = 0.54, 95% CI, 0.36-0.72). A lower positive cut point for the 2.0-mL NPM aliquot partially abrogated this minor difference. In 241 specimens diagnosed as low-grade and 31 as high-grade squamous intraepithelial lesions, there were no significant differences in HPVpositivity (>85% and 90%, respectively) between STP and NPM. NPM reduces specimen handling and decreases total testing time by approximately 33% without significant losses in HCII test performance.

J Natl Cancer Inst. 2005 Apr 20;97(8):577-86.

Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women.

Strickler HD, Burk RD, Fazzari M, Anastos K, Minkoff H, Massad LS, Hall C, Bacon M, Levine AM, Watts DH, Silverberg MJ, Xue X, Schlecht NF, Melnick S, Palefsky JM. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, 1300 Morris Park Ave., Belfer #1308, Bronx, NY 10461, USA. strickle@aecom.yu.edu

BACKGROUND: Little is known in human immunodeficiency virus (HIV)-positive women about how the combination of plasma HIV RNA level and CD4+ T-cell count is associated with the natural history of human papillomavirus (HPV) infection or about HPV reactivation--whether it occurs and with what frequency in HIV-positive women. METHODS: HIV-positive (n = 1848) and -negative (n = 514) women were assessed at semiannual visits (total person-years = 5661) for cervicovaginal HPV with polymerase chain reaction assays and for squamous intraepithelial lesions (SILs) by Pap smear. We studied the prevalent detection of HPV and SILs with generalized estimating equations and the incident detection and persistence of HPV and SILs with multivariable Cox models. All statistical tests were two-sided. RESULTS: We observed a strong interaction between the associations of CD4+ and plasma HIV RNA strata with both prevalent (P(interaction) = .002) and incident (P(interaction) = .001) detection of HPV. Indeed, the hazard ratio for incident HPV detection peaked between 4.0 and 5.0, with either a CD4+ count of less than 200 cells per mm3 or an HIV RNA level of more than 100,000 copies per mL. Although incident HPV detection in all women was associated with the number of recent sex partners (P(trend)<.001), 22% of sexually inactive HIV-positive women with a CD4+ count of less than 200 cells/mm3 also had at least one incidentally detected HPV type. The association between CD4+/HIV RNA strata and HPV persistence was statistically significantly smaller (P<.001) than for incident HPV detection. SIL prevalence, incident detection, and persistence had similar associations with CD4+/HIV RNA strata as HPV (above). CONCLUSION: In HIV-positive women, plasma HIV RNA level and CD4+ count in combination appear to have a strong and statistically interactive association with incident detection of HPV, some of which may reflect HPV reactivation (e.g., in sexually inactive women). The more moderate association between HIV coinfection and HPV persistence could partly explain why cervical cancer rates have not reached more epidemic proportions in HIV-positive women.

Genes Chromosomes Cancer. 2005 Jul;43(3):260-72.

A region on human chromosome 4 (q35.1-->qter) induces senescence in cell hybrids and is involved in cervical carcinogenesis.

Backsch C, Rudolph B, Kuhne-Heid R, Kalscheuer V, Bartsch O, Jansen L, Beer K, Meyer B, Schneider A, Durst M. Gynakologische Molekularbiologie, Abteilung Frauenheilkunde, Frauenklinik der Friedrich-Schiller-Universitat Jena, Germany.

Human papillomavirus (HPV) types 16 and 18 are known to play a major role in cervical carcinogenesis. Additional genetic alterations are required for the development and progression of cervical cancer. Previously, we showed that the introduction of an entire human chromosome 4 into HPV-immortalized cells by microcell-mediated chromosome transfer (MMCT) can induce senescence in cell hybrids. In the present study, we established eight new murine donor cell lines harboring different fragments of the human chromosome 4. These were tested for their ability to induce senescence by MMCT into HPV16-immortalized keratinocytes (HPK II) and cervical carcinoma cells (HeLa). By exclusion, we could identify a region for a putative senescence gene or genes at 4q35.1-->qter. Further evidence that this locus may be involved in cervical carcinogenesis was obtained by studying sections of high-grade cervical intraepithelial neoplasias (CIN2/3) and cervical cancers from 87 women using a combination of interphase fluorescence in situ hybridization (I-FISH) and microsatellite PCR. I-FISH indicated copy number loss at 4q34-->qter. Microsatellite analysis showed that loss of one or more alleles at chromosome 4 was more frequent in the cervical carcinomas than in the CINs. Loss of heterozygosity (LOH) affected four areas, D4S412 (4p16.3), D4S2394 (4q28.2), D4S3041 (4q32.3), and D4S408 (4q35.1), and was highest at D4S408. LOH at terminal 4q has been reported previously for cervical carcinomas and other human malignancies. This is the first report associating allelic loss at 4q34-->qter with high-grade intraepithelial neoplasia and cervical carcinoma, and the first experimental evidence that this locus or these loci can induce senescence in cervical carcinoma cells and HPV16-immortalized cells. (c) 2005 Wiley-Liss, Inc.

nt J STD AIDS. 2005 Mar;16(3):247-51.

Human papillomavirus prevalence at the USA-Mexico border among women 40 years of age and older.

Giuliano AR, Papenfuss MR, Denman CA, de Zapien JG, Abrahamsen M, Hunter JB. The Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. agiuliano@azcc.arizona.edu

The incidence of cervical cancer increases with age among USA Hispanics and women living in Latin America starting in the fourth decade of life. We conducted a study of women > or = 40 living at the USA-Mexico border to determine the prevalence and risk factors for human papillomavirus (HPV) infection detected by polymerase chain reaction. In all, 9.2% of participants tested HPV positive. Compared with women aged 50-59, odds ratios of 8.82 and 6.67 were observed for women > or = 60 and 40-49, respectively. Among women aged 40-49, both oncogenic and non-oncogenic HPV infections were detected; however, women > or = 60 were positive for predominantly oncogenic genotypes. HPV risk significantly increased with > or = 2 lifetime sexual partners in adjusted models. These data suggest that the prevalence of HPV infection may have a second peak among post-menopausal Hispanic women.

Br J Cancer. 2005 May 9;92(9):1794-9.

Human papillomavirus infection in women who develop high-grade cervical intraepithelial neoplasia or cervical cancer: a case-control study in the UK.

Grainge MJ, Seth R, Coupland C, Guo L, Rittman T, Vryenhoef P, Johnson J, Jenkins D, Neal KR. 1Division of Epidemiology and Public Health, School of Community Health Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, UK.

Human papillomavirus (HPV) testing might identify older women who could be withdrawn from the cervical screening programme, or require less frequent screening. A case-control study using the United Kingdom cervical screening population was set up to help address this issue. Cases comprised 575 women who developed cervical intraepithelial neoplasia (CIN) grade 2 or worse over a 13-year period following a cytologically normal baseline smear, and were stratified by age group ('under 20', '20-39' and 40 years or over). Controls (n=601) were women who remained disease free over this interval and were the same age on average as cases. DNA was extracted from the baseline smears and tested for HPV by PCR using GP5+/6+ consensus primers. HPV+ samples were tested for HPV types 16 and 18 using specific PCR primers. In all, 27.0% of cases tested positive for HPV at baseline, compared with 15.4% of controls (odds ratio (OR)=2.00; 95% confidence interval (CI), 1.50-2.68). Among women aged 40 years or over, the OR for HPV 16 was 8.95 (95% CI, 2.63-30.4). These results support the need for further cervical screening of HPV- older women, as many of the cases were HPV- at baseline.British Journal of Cancer (2005) 92, 1794-1799. doi:10.1038/sj.bjc.6602538 www.bjcancer.com Published online 12 April 2005.

Med Arh. 2005;59(1):47-51.

Prevalence of human papillomavirus infection in Slovenian women with repeated Pap II smears

HPV Virus Medical - Article in Bosnian

In the detection of precancerous lesions the cervical Papanicolaou smear screening is used in Slovenia and worldwide. Management of patients with repeat abnormal smears (Pap II) represents a great and complex clinical and public health problem. Repeated cytologic examinations are routine procedure in many countries, also in Slovenia, although the sensitivity of Pap smear testing in the detection of cervical intraepithelial neoplasia (CIN) II and III is relatively low. In cases of abnormal squamous cells and mildly dyskaryotic cells the presence of infections with high-risk HPV genotypes is being increasingly used as a complementary method to Pap smear testing. In the study we enrolled 148 cervical samples of women who within two years had three subsequent Pap II smears (abnormal squamous cells or mildly dyskaryotic cells). The prevalence of HPV infections was determined using three molecular tests: Hybrid Capture 2 (hc2) test and two variants of polymerase chain reaction (PCR-PGMY11/PGMY09 and PCR-CPI/CPIIG). HPV infection was detected in 25.7% of women. In women aged < or = 30 years a statistically significant higher prevalence of HPV infections was found (37.8%) than in women aged > 30 years (20.4%). Our findings show that repeat Pap smear as the method of follow-up and detection of precancerous lesions of the observed population do not provide relevant results due to low prevalence of HPV infections in Slovenia, which indirectly indicates low sensitivity and specificity of Pap smear testing. In the detection of HPV infections, molecular methods are thus sensitive screening tests to be used complementary to cytologic tests in women with abnormal squamous cells and mildly dyskaryotic cells.

HPV Virus Medical - HPV Research Links

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Human Papilloma Virus (HPV) and Genital Warts - Read a large article on HPV and how to live with it.